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De novo mutations in moderate or severe intellectual disability.

Hamdan FF, Srour M, Capo-Chichi JM, Daoud H, Nassif C, Patry L, Massicotte C, Ambalavanan A, Spiegelman D, Diallo O, Henrion E, Dionne-Laporte A, Fougerat A, Pshezhetsky AV, Venkateswaran S, Rouleau GA, Michaud JL - PLoS Genet. (2014)

Bottom Line: A total of 12 likely pathogenic DNMs were identified in genes previously associated with ID (ARID1B, CHD2, FOXG1, GABRB3, GATAD2B, GRIN2B, MBD5, MED13L, SETBP1, TBR1, TCF4, WDR45), resulting in a diagnostic yield of ∼29%.Protein network analysis indicated that the products of many of these known and candidate genes interact with each other or with products of other ID-associated genes further supporting their involvement in ID.We conclude that DNMs represent a major cause of moderate or severe ID.

View Article: PubMed Central - PubMed

Affiliation: CHU Sainte-Justine Research Center, Montreal, Canada.

ABSTRACT
Genetics is believed to have an important role in intellectual disability (ID). Recent studies have emphasized the involvement of de novo mutations (DNMs) in ID but the extent to which they contribute to its pathogenesis and the identity of the corresponding genes remain largely unknown. Here, we report a screen for DNMs in subjects with moderate or severe ID. We sequenced the exomes of 41 probands and their parents, and confirmed 81 DNMs affecting the coding sequence or consensus splice sites (1.98 DNMs/proband). We observed a significant excess of de novo single nucleotide substitutions and loss-of-function mutations in these cases compared to control subjects, suggesting that at least a subset of these variations are pathogenic. A total of 12 likely pathogenic DNMs were identified in genes previously associated with ID (ARID1B, CHD2, FOXG1, GABRB3, GATAD2B, GRIN2B, MBD5, MED13L, SETBP1, TBR1, TCF4, WDR45), resulting in a diagnostic yield of ∼29%. We also identified 12 possibly pathogenic DNMs in genes (HNRNPU, WAC, RYR2, SET, EGR1, MYH10, EIF2C1, COL4A3BP, CHMP2A, PPP1CB, VPS4A, PPP2R2B) that have not previously been causally linked to ID. Interestingly, no case was explained by inherited mutations. Protein network analysis indicated that the products of many of these known and candidate genes interact with each other or with products of other ID-associated genes further supporting their involvement in ID. We conclude that DNMs represent a major cause of moderate or severe ID.

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Number of DNMs per affected individual in each trio.
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pgen-1004772-g001: Number of DNMs per affected individual in each trio.

Mentions: We performed exome sequencing in 41 individuals with ID and their unaffected parents. We identified a total of 83 putative DNMs in as many genes within both coding and consensus splice site sequences. Sanger sequencing confirmed 81 of these as de novo and 2 as inherited from one of the parents (Table S1). All of these DNMs were represented by ≥25% of reads, suggesting that they are unlikely to be associated with somatic mosaicism. The fact that the mutant and wild-type peaks on Sanger chromatograms were comparable in size is consistent with this conclusion. The average DNM rate per trio was 1.98, with only 3 trios containing no detectable DNMs (Figure 1). The observed de novo SNV rate in the consensus coding sequences (CCDS) was 1.56 events per trio or 2.58×10−8 per base per generation (64 SNVs in 2,477,702,175 CCDS bases sequenced at ≥10× in the 41 affected individuals), which is significantly higher than the expected population rate of 1.65×10−8 (R binomial test, p = 0.0007), or than the ones experimentally determined from exome sequencing studies in control trios (1.28×10−8 and 1.51×10−8) [2], [4]. Considering only de novo SNVs affecting the coding and the canonical splice sites (AG, GT at intronic positions −1/−2 and +1/+2 of the acceptor and donor splice sites, respectively), 73% were missense and 11% were nonsense and canonical splice site mutations. We found a significant excess of these de novo nonsense and splice site mutations in the probands of our cohort when compared to data from exome sequencing of 54 control trios with no family history of ID [4], [11] or of 593 quartets, including unaffected siblings of individuals with ASD (R binomial test, p = 0.0015 and p = 0.02, respectively) (Table 1) [7], [9], [10]. Such an excess of deleterious DNMs suggest that at least a subset of them are pathogenic.


De novo mutations in moderate or severe intellectual disability.

Hamdan FF, Srour M, Capo-Chichi JM, Daoud H, Nassif C, Patry L, Massicotte C, Ambalavanan A, Spiegelman D, Diallo O, Henrion E, Dionne-Laporte A, Fougerat A, Pshezhetsky AV, Venkateswaran S, Rouleau GA, Michaud JL - PLoS Genet. (2014)

Number of DNMs per affected individual in each trio.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4214635&req=5

pgen-1004772-g001: Number of DNMs per affected individual in each trio.
Mentions: We performed exome sequencing in 41 individuals with ID and their unaffected parents. We identified a total of 83 putative DNMs in as many genes within both coding and consensus splice site sequences. Sanger sequencing confirmed 81 of these as de novo and 2 as inherited from one of the parents (Table S1). All of these DNMs were represented by ≥25% of reads, suggesting that they are unlikely to be associated with somatic mosaicism. The fact that the mutant and wild-type peaks on Sanger chromatograms were comparable in size is consistent with this conclusion. The average DNM rate per trio was 1.98, with only 3 trios containing no detectable DNMs (Figure 1). The observed de novo SNV rate in the consensus coding sequences (CCDS) was 1.56 events per trio or 2.58×10−8 per base per generation (64 SNVs in 2,477,702,175 CCDS bases sequenced at ≥10× in the 41 affected individuals), which is significantly higher than the expected population rate of 1.65×10−8 (R binomial test, p = 0.0007), or than the ones experimentally determined from exome sequencing studies in control trios (1.28×10−8 and 1.51×10−8) [2], [4]. Considering only de novo SNVs affecting the coding and the canonical splice sites (AG, GT at intronic positions −1/−2 and +1/+2 of the acceptor and donor splice sites, respectively), 73% were missense and 11% were nonsense and canonical splice site mutations. We found a significant excess of these de novo nonsense and splice site mutations in the probands of our cohort when compared to data from exome sequencing of 54 control trios with no family history of ID [4], [11] or of 593 quartets, including unaffected siblings of individuals with ASD (R binomial test, p = 0.0015 and p = 0.02, respectively) (Table 1) [7], [9], [10]. Such an excess of deleterious DNMs suggest that at least a subset of them are pathogenic.

Bottom Line: A total of 12 likely pathogenic DNMs were identified in genes previously associated with ID (ARID1B, CHD2, FOXG1, GABRB3, GATAD2B, GRIN2B, MBD5, MED13L, SETBP1, TBR1, TCF4, WDR45), resulting in a diagnostic yield of ∼29%.Protein network analysis indicated that the products of many of these known and candidate genes interact with each other or with products of other ID-associated genes further supporting their involvement in ID.We conclude that DNMs represent a major cause of moderate or severe ID.

View Article: PubMed Central - PubMed

Affiliation: CHU Sainte-Justine Research Center, Montreal, Canada.

ABSTRACT
Genetics is believed to have an important role in intellectual disability (ID). Recent studies have emphasized the involvement of de novo mutations (DNMs) in ID but the extent to which they contribute to its pathogenesis and the identity of the corresponding genes remain largely unknown. Here, we report a screen for DNMs in subjects with moderate or severe ID. We sequenced the exomes of 41 probands and their parents, and confirmed 81 DNMs affecting the coding sequence or consensus splice sites (1.98 DNMs/proband). We observed a significant excess of de novo single nucleotide substitutions and loss-of-function mutations in these cases compared to control subjects, suggesting that at least a subset of these variations are pathogenic. A total of 12 likely pathogenic DNMs were identified in genes previously associated with ID (ARID1B, CHD2, FOXG1, GABRB3, GATAD2B, GRIN2B, MBD5, MED13L, SETBP1, TBR1, TCF4, WDR45), resulting in a diagnostic yield of ∼29%. We also identified 12 possibly pathogenic DNMs in genes (HNRNPU, WAC, RYR2, SET, EGR1, MYH10, EIF2C1, COL4A3BP, CHMP2A, PPP1CB, VPS4A, PPP2R2B) that have not previously been causally linked to ID. Interestingly, no case was explained by inherited mutations. Protein network analysis indicated that the products of many of these known and candidate genes interact with each other or with products of other ID-associated genes further supporting their involvement in ID. We conclude that DNMs represent a major cause of moderate or severe ID.

Show MeSH
Related in: MedlinePlus